Innate immunity is the first line of defense that protects the host from invading pathogens, including HIV. HIV viremia is associated with a wide range of immune dysfunctions that contribute to an immunocompromised state and disease progression. Persistent HIV replication exhibits a broad effect on several immune cell types and/or their interactions involved in mounting an effective immune response. We have previously described several NK-cell abnormalities in HIV-viremic individuals. In the past year, we investigated the integrity of plasmacytoid dendritic cell (pDC)-NK cell interactions among HIV viremic, aviremic and seronegative individuals. Our results describe: 1) a critical defect in the ability of pDCs from HIV-infected individuals to secrete IFN-&#61537;and TNF and subsequently activate NK cells and 2) an inherent defect in NK cells from HIV-infected individuals to respond to pDC-secreted cytokines. Furthermore, we demonstrated a direct effect of HIV trimeric gp120 on NK cells in vitro similar to that described ex vivo. Finally, we established that HIV gp120-mediated suppression of NK cells results from its binding to the integrin alpha4beta7 expressed on NK cells. These findings suggest a novel mechanism by which HIV suppresses innate immune function in infected individuals.